María-Victoria Mateos

IBSAL-University Hospital of Salamanca

Spain

Clinical research in Multiple Myeloma

COMy award

University of Salamanca

Sagar Lonial CV

Nikil Munshi CV

95 pages

Maria Victoria Mateos CV

Dr. Maria-Victoria Mateos, MD, PhD, is Consultant Physician in the Haematology

Department and Associate Professor of Medicine at the University of Salamanca,

Spain. She is the director of the Myeloma Program and coordinates the Clinical

Trials Unit in Salamanca’s University Hospital Haematology Department.

She serves as coordinator of GEM (Spanish Myeloma Group), with direct

involvement in the design and development of clinical trials. She has coordinated

many clinical trials in elderly and smouldering MM patients that have profoundly

influenced current options for treating these patient populations.

She has published over 200 original papers in international journals. Her areas of

interest include multiple myeloma, the biology of plasma cells and the news drugs

development.

Short document

María-Victoria Mateos

IBSAL-University Hospital of Salamanca

Spain

University of Salamanca

Contributions to the diagnostic and

management of Multiple Myeloma patients

PET:VEL 2004-> velcade-melfalan-prednisone*

MM1S Cell line: In vitro anti-myeloma activity of Bortezomib

+ melphalan + dexamethasone

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MT

T u

pta

ke (

A5

70)

Dex 100 nM

Melphalan 1 uM

Bortezomib 2 nM

V-MP : Treatment scheduleDay

1 2 3 4 8 11 22 25 29 32 33–42

█ █ █ █ █ █ █ █

█ █ █ █

█ █ █ █

Day

1 2 3 4 8 15 22 23–35

█ █ █ █

█ █ █ █

█ █ █ █

Bortezomib

Melphalan 9 mg/m2

Prednisone 60 mg/m2

• Four 6-week cycles

• Five 5-week cycles

Bortezomib

Melphalan 9 mg/m2

Prednisone 60 mg/m2

Rest p

erio

d

Rest p

erio

d

• Total = 49 weeks of treatmentMateos et al. Blood 2006;108:2165–72

V-MP: Response rates (n=53)

Analysis of the best response so far achieved

1st cycle V-MP

70%

0%

10%

20%

30%

40%

50%

60%

70%

CR IF- CRIF+ PR MR SD

6% 2%

62%

6%

24%

Best response: median 5 cycles (2-9)

86%

30%

13%

43%

13%

0%

10%

20%

30%

40%

50%

60%

70%

CR IF- CR IF+ PR SD

Mateos et al. Blood 2006;108:2165–72

Conclusions

High efficacy of V-MP:

- 43% CR/nCR (30% CR IF-, half of them by immunophenotype)

- Early responses (1-3 cycles)

- Response is not influenced by cytogenetic abnormalities

Acceptable toxicity:

– Similar to the one described in previous studies in refractory MM

– More hematological toxicity (attributable to Melphalan)

– Higher in patients >75 years

– Toxicity decreases from the 3rd cycle

Rationale for experimental arm of Phase III VISTA Trial: V-MP vs MP

VISTA: VELCADE as Initial Standard Therapy in multiple

myeloma: Assessment with melphalan and prednisone

VMPCycles 1-4

Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32

Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

Cycles 5-9

Bortezomib 1.3 mg/m2 IV: days 1,8,22,29

Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

MPCycles 1-9

Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

R

A

N

D

O

M

I

Z

E

9 x 6-week cycles (54 weeks) in both arms

Randomized, international, phase III trial of VMP vs MP in previously

untreated MM patients who were not candidates for HDT-ASCT

Patients: Symptomatic multiple myeloma/end organ damage with

measurable disease (N, 682)

▪ ≥65 yrs or <65 yrs and not transplant-eligible; KPS ≥60%

Primary Endpoint: TTP

Secondary Endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL (PRO)

San Miguel et al. JCO 2013; 31(4):448-55

TTP OS

0 3 6 9 12

Time (months)

15 18 21 24 27

0

20

40

60

80

100

VMP

MP

Patie

nts

withou

t even

t (%

)

VMP: 24.0 months

MP: 16.6 months, P<0.000001

MP + Bortezomib (VMP) vs MP: VISTA

RR (CR) (%): 71(30) vs 35(4)

0 6 12 18 24 30 36 42 48 54 60 66 72 78

Patie

nts

withou

t even

t (%

)

Median follow-up 60 months

Median OS:

VMP: 56m

MP: 43m, P=0.0008

Median OS benefit: 13.3 m100

90

80

70

60

50

40

30

20

10

0

Time (months)

G3-4 AEs: GI (19%), PN (13%), VVZ react (3%)

Bortezomib twice a week x 4cycles + weekly x 5cycles

VMP is one standard of care

VISTA trial: 682 patients 151 investigators in 22 countries

What was the next step?

Modified VMP vs VTP followed by maintenance with VT or VP in

newly diagnosed elderly MM patients (PETHEMA/GEM05 >65y study)

Aim: To reduce the toxicity of standard VMP (by using a weekly schedule of Bz and only 6

cycles) & to maintain the efficacy ( with a prolonged maintenance)

Induction

x6 cyclesBz weekly

except in the 1st

Bort/Mel/Pred

(VMP)

Bort/Thal/Pred

(VTP)vs

Mateos et al. ASH 2009 (abstract (3)

Mateos MV et al. Lancet Oncology 2010

Maintenance

x3 yearsBz / 3m *

Bort/Thal

(VT)

Bort/Pred

(VP)

Bort/Thal

(VT)

Bort/Pred

(VP)

2ª Aim at maintenance: to compare VT vs VP

*Bz: 1,3mg d 1,4,8,11 / 3m; Thal: 50mg d; Pr: 50mg alternting days

Comparison between GEM 2005 and VISTA

1. More discontinuations with VTP (17%) and more SAEs (15%VMP/ 30%VTP).

2. No differences in RR between VMP & VTP

3. Increase in CR from 23% after induction to 42% with Maintenance

4. TTP/PFS are bodeline superior for VT > VP (p 0,05).

GEM 2005 (260 pts) VISTA (344 pts)

Neuropathy (G3) 5% 13%

G-I (G3) 7% 19%

Discontinuations 11%1 17%

PR 80%2 75%

CR 42%3 30%

PFS 314 21 m

OS (at 3 y) 70% 67%

Mateos et al. Lancet Oncology 2010; 10(11): 934-41 San Miguel et al. N Engl J Med 2008; 359(9):906-17

ASH2009: Plenary session

Conclusions

• Alkylating agents should remain as important drugs in the treatment

armamentarium of elderly untreated elderly MM patients

• The weekly shedule of Bort significantly reduced the incidence of PN

• Maintenance therapy was able to increase the CR rate with a low toxicity

profile. VT was superior in terms of TTEvents.

(GEM05>65)

What else we did?

New standards of care for elderly MM patients

MPT

MP

VMP

Alkylators-based

regimens

Alkylators-free

regimens

Len-dex

IMiD’s

Six randomized trials:

Benefit in PFS&OS...6mOne randomized trial:

Benefit in PFS...8m

OS...13m

Fayers PM et al. Blood 2011; 118(5): 1239-47San Miguel. N Engl J Med 2008;359:906-17

San Miguel . J Clin Oncol. 2013; 31: 448-55

One randomized trial:

Benefit in PFS&OS vs MPT

Benboubker L, et al. NEJM 2014; 371: 906-17

Study design and hypothesis: VMP/Rd

Symptomatic newly diagnosed MM pt > 65 y

* Half of the patients will start by VMP and half by Rd

MPV x 9cycles Lendex x 9 cycles

MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd

Sequential scheme

Alternating scheme*

N: 240 pts74 weeks

Hypothesis: - Higher efficacy for the alternating scheme

- Less probability of cell tumor scape

- Lower cumulative toxicity

Mateos MV et al. Blood 2016

Outcome in terms of PFS and OS in patients who

completed 18 cycles (n:138)

Median follow-up: 30 m (9-43)

OS

Sequential : 91% at 3 yrs

Alternating: 95% at 3 yrs

PFS

Sequential: 52% at 3y

Alternating: 60% at 3y

p=NS

20,0010,000,00

0,2

454035302520151050

1,0

0,8

0,6

0,4

0,2

0,0

454035302520151050

1,0

0,8

0,6

0,4

0,2

0,0 p=NS

Mateos MV et al. Blood 2016

Future of the treatment for elderly MM patients

MP

VMP

Alkylators-based

regimens

Alkylators-free

regimens

Len-dex

IMiD’s

Spanish standard of care for ”fit” elderly NDMM patients

It is necessary to individualize the treatment in elderly patients

according to the frailty

GEM2017FIT

2

aDuring the first cycle (6 weeks), bortezomib is given on D1, 4, 8, 11, 22, 25, 29, and 32.; GAH: J Geriatr Oncol. 2015 Sep;6(5):353-61; R1: first randomization; R2:

second randomization ; IMF imnunofenotipic response NGF ( next generation flow)

NDMM

patients

NS CTC

>65 y

n= 462

elderly

Fit

Patients

(GHA) ARM 2a KRd .N=154

CFZ: 20/70 mg/m2, d1, 8, 15

LEN: 25 mg, d1–21

DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23

18 28-day cycles

N=159

ARM 1 VMP N=154

Mel: 9mg/m2 D1-4

Pred: 60mg/m2 D1-4

BTZ: 1.3mg/m2 D1, 8,15,22ª

One 6 week cycle followed

by eight 4-week cycle

N=159

Rd

LEN: 25 mg, d1–21

DEX: 20/10 mg, d1, 2, 8, 9,

15, 16, 22, 23

Nine 28-day cycles

(R1) Induction 18 cycles (R2) MaintenanceConsolidation

Rd

LEN: 25 mg, d1–

21

DEX: 20/10 mg,

d1, 2, 8, 9, 15,

16, 22, 23

Dara 16 mg/Kg

Days 1, 8, 15, 22

of cycles 1-2; Days

1 and 15 of cycles

3 and 4

Four 28-day

cycles

Dara 16 mg/Kg IV Day 1 of cycles 1-24

+

R 15 mg, d1–21

Until progresion

No maintenance

MRD

9 cy

MRD

18 cy

MRD

22 cy

Dara 16 mg/Kg IV Day 1 of cycles 1-24

+

R 15 mg, d1–21

Until progresionARM 2b KRD- DARA n=154

CFZ: 20/70 mg/m2, d1, 8, 15

LEN: 25 mg, d1–21

DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23

Dara 16 mg/Kg IV Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15

of cycles 3 and 4; Day 1 of cycles 5 to 18

No maintenance

Primary endpoint immonuphenotipic complete response Secondary exploratory outcome: PFS

MRD+

MRD-

Directly to the R2

maintenance fase

*

*

* Patientes in Biological relapse will be rechallenge by Dra + R

MGUS or

smouldering

myeloma

Asymptomatic Symptomatic

ACTIVE

MYELOMA

M p

rote

in (

g/L

)

20

50

100

1st RELAPSE

2nd RELAPSE

REFRACTORY

RELAPSE

First-line therapy

Plateau

remission

Second-line therapy Third-line therapy

Multiple myeloma:

natural history of disease

Durie BGM, ed. Multiple Myeloma Concise Review 2007. International

Myeloma Foundation. American Cancer Society.

Cancer Facts & Figures, 2008.MGUS, monoclonal gammopathy of unknown significance; M protein, myeloma protein.

Does make sense thinking in early treatment for asymptomatic myeloma?

Smoldering Multiple Myeloma: Management

AgentsORR (%)

TTP OS Reference

Early MP* vs

Deferred MP

52

55

No

benefit

No

benefit

Hjorth M, et al. Eur J Haematol. 1993

Grignani G, et al. Br J Cancer. 1996

Riccardi A, et al. Br J Cancer. 2000

Thal+Zol vs

Zol**

37

0

No

benefit

No

benefitWitzig TE, et al. Leukemia 2013

Bisphosphonates***vs

observation0

No

benefit

No

benefit

Martin A, et al. Br J Haematol. 2002

D’arena et al. Leuk Lymphoma. 2011

Musto P, et al. Cancer. 2008

*Abandon: No differences in survival and potential risk of secondary leukemias

**Low efficacy&high rates of discontinuation due to PN

***Skeletal related events lower in the bisphosphonate groups (39% vs 73% and 55% vs 78%)

Smoldering Multiple Myeloma: Management

AgentsORR (%)

TTP OS Reference

Early MP* vs

Deferred MP

52

55

No

benefit

No

benefit

Hjorth M, et al. Eur J Haematol. 1993

Grignani G, et al. Br J Cancer. 1996

Riccardi A, et al. Br J Cancer. 2000

Thal+Zol vs

Zol**

37

0

No

benefit

No

benefitWitzig TE, et al. Leukemia 2013

Bisphosphonates***vs

observation0

No

benefit

No

benefit

Martin A, et al. Br J Haematol. 2002

D’arena et al. Leuk Lymphoma. 2011

Musto P, et al. Cancer. 2008

*Abandon: No differences in survival and potential risk of secondary leukemias

**Low efficacy&high rates of discontinuation due to PN

***Skeletal related events lower in the bisphosphonate groups (39% vs 73% and 55% vs 78%)

Low, intermediate and high risk patients were included

QuiRedex: Study Design

• Multicenter, open-label, randomized phase III trial

Patients with

high-risk

smouldering

MM

(N = 125)

Lenalidomide 25 mg/day on

Days 1-21 +

Dexamethasone 20 mg/day on

Days 1-4, 12-15

No Treatment No Treatment

Lenalidomide

10 mg/day on Days 1-21

(Low-dose dexamethasone

added at time of

biologic progression)

Induction

9 x 28-day cycles

Maintenance

28-day cycles

2 yrs

High-risk was defined according to the Mayo and/or Spanish models

In both arms, blood counts, biochemical analysis (including creatinine and calcium) and

serum/urine levels of MC were performed monthly. Skeletal survey was performed during the

screening phase and thereafter only if clinical symptoms emerged.

Mateos MV, et al. NEJM 2013; 369:438-47

Len-dex vs no treatment: TTP to active disease (n = 119)

Per-protocol Patients population

Mateos MV, et al. NEJM 2013

Median follow-up: 40 m

Mateos MV, et al. Lancet Oncology 2016

Median follow-up: 75 m

Treatment Group

Observation Group

Hazard ratio for progression: 0·24, p<0·0001

Len-dex vs no treatment: OS from inclusion

(n = 119)

Median follow-up: 40 m

Mateos MV, et al. NEJM 2013 Mateos MV, et al. Lancet Oncology 2016

Median follow-up: 75 m

Treatment Group

Observation Group

Hazard ratio for death: 0·43, p=0·024

Rajkumar et al. Lancet Oncology 2014; 15: e538-48

Subgroup of SMM patients that require be treated

Current studies in High-risk Smouldering Multiple

Myeloma

• Numerous clinical trials (51 in clinicaltrials.gov) with several

drugs are currently ongoing in this group of patients

• To prevent the progression to Myeloma

- R alone, Elo-Rd, Daratumumab, KRd, Ixazomib-Rd,

pembrolizumab, nivolumab-Rd, isatuximab,…

• To completely erradicate the tumor clone

- CESAR trial

- ASCENT trial

Curative Estrategia Smouldering Alto Riesgo (CESAR trial)(n:90)

Induction 6 cycles of KRd

ASCT (melphalan 200)

Maintenance (Len-dex for 2yrs)

Consolidation (2 cycles of KRd)

Primary objective: To evaluate the proportion of patients in sustained

immunophenotypic response at 5 years

Hypothesis: At least 50% of patients will achieve the objective20 centers

MRD

MRD

MRD

MRD

Role of depth of response

Depth of response is related to TTP, PFS and OS

Depth of response Time to progression

MR

PR

VGPR

nCR

CR

sCR

Treatment Initiation

Time

MR, minimal response; sCR, stringent complete response; iCR, immunophenotypic CR; TTP, time to progression.

CR is a typical endpoint and one of the most

powerful prognostic markers in MM

Pro

gre

ssio

n-f

ree s

urv

ival (%

)

Time from diagnosis (months)

CR (n=578) median PFS: 54 months

nCR (n=273) median PFS: 43

months

PR (n=553) median PFS: 33 months

<PR (217) median PFS: 15 months

100

80

60

40

20

0

0 50 100 150 200

P <.001

CR vs nCR: P

=.002

nCR vs PR: P =.001

PR vs <PR: P <.001

Overa

ll surv

ival (%

)Time from diagnosis (months)

CR (n=578) median OS: 103 months

nCR (n=273) median OS: 86 months

PR (n=553) median OS: 72 months

<PR (217) median OS: 25 months

P <.001

CR vs nCR: P

=.124

nCR vs PR: P =.001

PR vs <PR: P <.001

100

80

60

40

20

0

0 50 100 150 200

GEM2000, GEM2005MENOS65, GEM2005MAS65,

GEM2010MAS65

But the true value of CR relies in the MRD

status, and CR w/o MRD is no better than PR

Pro

gre

ssio

n-f

ree s

urv

ival (%

)

Time from diagnosis (months)

MRD- (n=326) median PFS: 71 months

CR (n=133) median PFS: 36 months

nCR (n=99) median PFS: 32 months

PR (n=211) median PFS: 35 months

<PR (48) median PFS: 21 months

P <.001

MRD- vs CR: P

<.001

CR vs nCR: P =.149

nCR vs PR: P =.607

PR vs <PR: P =.001

Overa

ll surv

ival (%

)Time from diagnosis (months)

MRD- (n=326) median OS: Not

reached

CR (n=133) median OS: 68 months

nCR (n=99) median OS: 73 months

PR (n=211) median OS: 68 months

<PR (48) median OS: 46 months

P <.001

MRD- vs CR: P <.001

CR vs nCR: P =.701

nCR vs PR: P =.667

PR vs <PR: P =.037

100

80

60

40

20

0

0 50 100 150 200

100

80

60

40

20

0

0 50 100 150 200

GEM2000, GEM2005MENOS65, GEM2005MAS65,

GEM2010MAS65

MRD was evaluated by flow cytometry

Martinez-Lopez J, et al. Blood. 2014;123:3073-3079

Tim

e-t

o p

rogre

ssio

n (

%)

100

80

60

40

20

0

100 1500 50

P = .001

CR & MRD –( n = 26)

CR & MRD + (n = 36)

Months

median 131m

median 35m

MRD monitoring using NGS is relevant

58% of the patients in conventionally-defined CR had positive MRD by NGS

Kumar S et al. Lancet 2016

Acknowledgments: Investigators of GEM

Chairs: MVM, Jesús San Miguel, Joan Bladé and JJ Lahuerta

Acknowledgments: GEM/Pethema

Support for data management: Arturo Touchard/Roberto Maldonado

Acknowledgments: Patients

Asociaciones locales de

cada ciudad/region por

el soporte

Acknowledgments: pharmaceutical companies

SAR650984Isatuximab

IxazomibNinlaro®

ElotuzumabEmpliciti™

PanobinostatFarydak®

DaratumumabPembrolizumab

Keytruda

MK-3475

Durvalumab

Carfilzomib

Nivolumab

Acknowledgments: Hematology Department

Acknowledgments: Hematology Department

Acknowledgments: Myeloma team

Norma Gutiérrez, Ramón Garcia-Sanz, Verónica González, Noemi Puig, Mercedes

Garayoa,Teresa Paino,…..

Acknowledgments: family

Acknowledgments: Rafa, Rafa, Marta y Juan